Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer.

Carcinogenesis ·第 36 卷 ·第 11 期 ·2016-02-03

Lawrenson Kate, Iversen Edwin S, Tyrer Jonathan, Weber Rachel Palmieri, Concannon Patrick, Hazelett Dennis J, Li Qiyuan, Marks Jeffrey R, Berchuck Andrew, Lee Janet M, Aben Katja K H, Anton-Culver Hoda, Antonenkova Natalia, , , Bandera Elisa V, Bean Yukie, Beckmann Matthias W, Bisogna Maria, Bjorge Line, Bogdanova Natalia, Brinton Louise A, Brooks-Wilson Angela, Bruinsma Fiona, Butzow Ralf, Campbell Ian G, Carty Karen, Chang-Claude Jenny, Chenevix-Trench Georgia, Chen Ann, Chen Zhihua, Cook Linda S, Cramer Daniel W, Cunningham Julie M, Cybulski Cezary, Plisiecka-Halasa Joanna, Dennis Joe, Dicks Ed, Doherty Jennifer A, Dörk Thilo, du Bois Andreas, Eccles Diana, Easton Douglas T, Edwards Robert P, Eilber Ursula, Ekici Arif B, Fasching Peter A, Fridley Brooke L, Gao Yu-Tang, Gentry-Maharaj Aleksandra, Giles Graham G, Glasspool Rosalind, Goode Ellen L, Goodman Marc T, Gronwald Jacek, Harter Philipp, Hasmad Hanis Nazihah, Hein Alexander, Heitz Florian, Hildebrandt Michelle A T, Hillemanns Peter, Hogdall Estrid, Hogdall Claus, Hosono Satoyo, Jakubowska Anna, Paul James, Jensen Allan, Karlan Beth Y, Kjaer Susanne Kruger, Kelemen Linda E, Kellar Melissa, Kelley Joseph L, Kiemeney Lambertus A, Krakstad Camilla, Lambrechts Diether, Lambrechts Sandrina, Le Nhu D, Lee Alice W, Cannioto Rikki, Leminen Arto, Lester Jenny, Levine Douglas A, Liang Dong, Lissowska Jolanta, Lu Karen, Lubinski Jan, Lundvall Lene, Massuger Leon F A G, Matsuo Keitaro, McGuire Valerie, McLaughlin John R, Nevanlinna Heli, McNeish Iain, Menon Usha, Modugno Francesmary, Moysich Kirsten B, Narod Steven A, Nedergaard Lotte, Ness Roberta B, Noor Azmi Mat Adenan, Odunsi Kunle, Olson Sara H, Orlow Irene, Orsulic Sandra, Pearce Celeste L, Pejovic Tanja, Pelttari Liisa M, Permuth-Wey Jennifer, Phelan Catherine M, Pike Malcolm C, Poole Elizabeth M, Ramus Susan J, Risch Harvey A, Rosen Barry, Rossing Mary Anne, Rothstein Joseph H, Rudolph Anja, Runnebaum Ingo B, Rzepecka Iwona K, Salvesen Helga B, Budzilowska Agnieszka, Sellers Thomas A, Shu Xiao-Ou, Shvetsov Yurii B, Siddiqui Nadeem, Sieh Weiva, Song Honglin, Southey Melissa C, Sucheston Lara, Tangen Ingvild L, Teo Soo-Hwang, Terry Kathryn L, Thompson Pamela J, Timorek Agnieszka, Tworoger Shelley S, Van Nieuwenhuysen Els, Vergote Ignace, Vierkant Robert A, Wang-Gohrke Shan, Walsh Christine, Wentzensen Nicolas, Whittemore Alice S, Wicklund Kristine G, Wilkens Lynne R, Woo Yin-Ling, Wu Xifeng, Wu Anna H, Yang Hannah, Zheng Wei, Ziogas Argyrios, Coetzee Gerhard A, Freedman Matthew L, Monteiro Alvaro N A, Moes-Sosnowska Joanna, Kupryjanczyk Jolanta, Pharoah Paul D, Gayther Simon A, Schildkraut Joellen M

摘要

Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10(-7)). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r (2) with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11-1.24, P = 1.1×10(-7)). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72×10(-8)). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r (2) = 0.99 with rs6005807) and CHEK2 expression (P = 2.70×10(-8)). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene.

文献信息

期刊

Carcinogenesis

期刊简称

Carcinogenesis

ISSN

0143-3334

发表日期

2016-02-03

收录日期

2015-10-30

更新日期

2016-12-09

语言

英语

国家/地区

England

NLM ID

8008055

外部链接

PubMed 原文查看期刊详情

分析服务

Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer.

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